DiGeorge syndrome (DGS)/velo-cardio-facial syndrome (VCFS) is one of the common genetic disorders and affects approximately one in 4000 livebirths. Hemizygosity of a 1.5-3.0 Mb region of the human 22q11 underlies various neuropsychiatric, behavioral and physical abnormalities in DGS/VCFS. They include behavioral excitation, impaired prepulse inhibition, social interaction problems, as well as cardiovascular defects. Although efforts have been made in identifying individual 22q11 genes responsible for the behavioral abnormalities of DGS/VCFS, little is known about how individual 22q11 genes interact in increasing the susceptibility to these behavioral abnormalities. We and others have shown that deletion of either the T-box transcription factor Tbx1 or Cdcrel (cell division control related protein, also called Sept5) induces some, but not all DGS/VCFS symptoms in mice. To study the interactive role of Tbx1 and Cdcrel, the Principal Investigator has developed a double Tbx1/Cdcrel heterozygous mouse. Using this mouse line together with Tbx1 heterozygous mice and Cdcrel heterozygous/knockout mice, we have further shown that mice with combined heterozygosity of Tbx1 and Cdcrel, but not mice with deletion of either Tbx1 or Cdcrel alone, have sensitized hyperactivity. This suggests that Tbx1 and Cdcrel synergistically increase the susceptibility to the behavioral abnormalities of DGS/VCFS. Our long-term goal is to ascertain the nature of interaction among 22q11 genes as one of the underlying mechanisms for the behavioral abnormalities of DGS/VCFS. The specific hypothesis to be tested in this R21 proposal is that Tbx1 and Cdcrel interactively contribute to distinct behavioral abnormalities in mice. The specific aims to test this hypothesis are: Specific Aim 1: To determine whether heterozygosity of Tbx1, Cdcrel, or their combination causes abnormalities in locomotor activity/habituation, prepulse inhibition and social behaviors in mice (Experiments 1- 3). We will use Tbx1 heterozygous mice, Cdcrel heterozygous and knockout mice, double Tbx1/Cdcrel heterozygous mice, and their wild-type littermates. Specific Aim 2: To determine whether behavioral abnormalities seen in double heterozygous mice are attenuated by restoration of Cdcrel by a viral vector in the brain (Experiment 4). The present R21 proposal will provide a mouse model to further ascertain the nature of interaction between Tbx1 and Cdcrel in the brain in relation to behavioral abnormalities. The proposal will form a solid basis to further study the genetic basis of this common developmental disorder. Because deletion of 22q11 is also associated with high rates of schizophrenia, obsessive compulsive disorder, and attention deficit hyperactivity disorder, the outcome of this project will have significant implications for a better understanding of the genetic mechanisms of these neuropsychiatric disorders as well. The proposed project will ascertain the role of two 22q11 genes in behavioral abnormalities in a double heterozygous mouse model. Because hemizygosity of this chromosomal region is associated with many neuropsychiatric disorders and behavioral abnormalities, the outcome of the proposed studies will contribute to a better understanding of the genetic mechanisms underlying neuropsychiatric disorders, including schizophrenia.